PROJECT SUMMARY/ABSTRACT Infants born preterm are nearly 20 times more likely to die compared to full term infants. Despite this, preterm birth (PTB) biological mechanisms remain incompletely understood and no treatment reliably prevents or halts the syndrome. Two thirds of PTBs are spontaneous (sPTB) and nearly half of severe sPTBs display evidence of an inflammatory origin. Yet, monitoring and targeting of infectious exposures and inflammatory plasma biomarkers neither predict nor prevent sPTB. Our highly novel pilot data suggest that biological signatures of the maternal immune response during non-laboring pregnancy may contribute to the prediction of future spontaneous birth timing as well as response to preventive intervention. The overall objective for this proposal is to determine whether our proposed immune markers can serve as novel predictors of sPTB risk which could be used in the future to design and test precision interventions aimed at preventing sPTB through normalization of maternal immune function. To test this hypothesis, we will prospectively enroll in early pregnancy and sample at two time points 150 pregnant women at risk for sPTB due to a prior history of sPTB, expecting > 30% to develop sPTB in this pregnancy. We will quantify maternal immune parameters and examine associations with future sPTB. We will perform statistical analyses to determine whether baseline biologic profiles modify the effect of clinically-delivered preventive intervention on pregnancy prolongation. We expect the ?Maternal Immune Responsiveness As CLinical target for preterm birth prevention? (MIRACL) study to result in data that shifts how we think about predicting sPTB and preventive intervention response. This work will inform the design of future clinical trials aimed at preventing sPTB. Under the mentorship of a superbly matched transdisciplinary team (immunobiology, prenatal epigenomics, prenatal translational science, bioinformatics), this grant will also allow me to achieve my career development goal of becoming an expert in prenatal immunobiology and an independent translational scientist with research focused on promoting the health of mothers and saving the lives of infants by developing immune-based precision health strategies to prevent complications of pregnancy.